Aim: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was ...to revise the diagnostic criteria for Japanese Werner syndrome.
Methods: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS.
Results: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted.
Conclusion: The 26‐year‐old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population. Geriatr Gerontol Int 2013; 13: 475–481.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The combination of sarcopenia, age-related loss of muscle strength and mass, and obesity has been recognized as a new category of obesity among the elderly. Given that leptin has been hypothesized to ...be involved in the pathogenesis of sarcopenic obesity, we investigated the relationship between plasma leptin levels and thigh muscle sarcopenia and visceral obesity. Thigh muscle cross-sectional area (CSA) and visceral fat area were measured using computed tomography as indices for muscle mass and visceral fat, respectively, in 782 middle-aged to elderly subjects (303 men and 479 women), participating in a medical check-up program. Visceral obesity was defined as visceral fat area >100 cm², and sarcopenia was defined as < (one standard deviation--mean of thigh muscle CSA/body weight of young subjects aged <50 years).Thigh muscle CSA was significantly and negatively associated with plasma levels of leptin in both men (β = -0.28, p<0.0001) and women (β = -0.20, p<0.0001), even after correcting for other confounding parameters, including age, body weight, body height, visceral fat area, blood pressure, homeostatic model assessment index, and high sensitive C reactive protein. Subjects were divided into four groups based on presence or absence of sarcopenia or visceral obesity. Plasma levels of leptin were higher in subjects with sarcopenic visceral obesity than in those with either sarcopenia or visceral obesity alone. These findings indicate that sarcopenic visceral obesity is a more advanced, and suggest that leptin may link visceral obesity and sarcopenia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Masked hypertension (HT) is a known risk factor for cardiovascular outcomes. Postural blood pressure (BP) dysregulation is another BP phenomenon representing cardiovascular frailty. Given their ...several shared risk factors, we suspected an inter-relationship between these two BP phenomena. Here we investigated a possible relationship between masked HT and postural BP dysregulation in a general population. Study subjects were 884 apparently healthy individuals (aged 66.3±8.9 years). Masked HT was assessed on the basis of the ambulatory monitored average awake BP and office-measured BP values. Orthostatic BP change was measured at our office after a subject was asked to actively stand up. A strong inverse relationship was noted for orthostatic systolic BP (SBP) change and office-to-awake SBP differences (office-awake BP) (r=-0.422, P<0.001), and these relationships were replicated in the second-visit measurements (n=101, r=-0.326, P=0.001). Multivariate analysis revealed that the inverse association was independent (β=-0.23, P<0.001) of possible covariates, including baseline office BP and antihypertensive treatment. Orthostatic HT (OHT), which is defined as postural increases in SBP >10 mm Hg, 3 min after standing (P=0.001), but not transient HT at only 1 min (P=0.767), was associated with greater office-to-awake SBP differences than in orthostatic normotensive subjects. Among apparently normotensive subjects, the frequency of masked HT was therefore significantly greater in subjects who showed OHT 3 min after standing (52.1%) compared with controls (27.5%) (odds ratio=3.01, P=0.001). We observed an intra-individual relationship between the postural BP change and the office-to-awake BP differences, and subjects who showed OHT were likely to have masked HT irrespective of antihypertensive treatment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background and aims While alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol ...levels is unclear. Aldehyde dehydrogenase 2 ( ALDH2 ) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers. Methods This study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy. Results Alcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men ( p < 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p < 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p < 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p < 0.001) and inversely associated with LDL particle numbers (−67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake. Conclusions Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK, ZRSKP
The aim of the present study was to examine how liver markers are associated with insulin resistance in Japanese community-dwelling adults.
This cross-sectional study included 587 men aged 58 ± 14 ...(mean ± standard deviation; range, 20-89) years and 755 women aged 60 ± 12 (range, 21-88) years. The study sample consisted of 998 (74.4%) non-obese body mass index (BMI) <25.0 kg/m2 and 344 (25.6%) overweight (BMI ≥ 25 kg/m2) subjects. Insulin resistance was defined by homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5, and HOMA-IR and potential confounders were compared between the groups. Areas under the curve (AUC) of the receiver operating characteristic curves (ROC) were used to compare the power of these serum markers.
In non-obese subjects, the best marker of insulin resistance was alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio of 0.70 (95% confidence interval (CI), 0.63-0.77). In overweight subjects, AUC values for the ALT/AST ratio and ALT were 0.66 (0.59-0.72) and 0.66 (0.59-0.72), respectively. Multiple linear regression analyses for HOMA-IR showed that ALT/AST ratios were independently and significantly associated with HOMA-IR as well as other confounding factors in both non-obese and overweight subjects. The optimal cut-off point to identifying insulin resistance for these markers yielded the following values: ALT/AST ratio of ≥ 0.82 in non-obese subjects and ≥ 1.02 in overweight subjects. In non-obese subjects, the positive likelihood ratio was greatest for ALT/AST ratio.
In non-obese Japanese adults, ALT/AST ratio may be the best reliable marker of insulin resistance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening
Yasuharu Tabara 1 ,
Haruhiko Osawa 2 ,
Ryuichi Kawamoto 3 ,
Hiroshi Onuma 2 ,
Ikki Shimizu 4 ,
...Tetsuro Miki 5 ,
Katsuhiko Kohara 5 and
Hideichi Makino 2
1 Department of Basic Medical Research and Education, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
2 Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
3 Department of Internal Medicine, Seiyo City Nomura Hospital, Seiyo City, Ehime, Japan
4 Department of Internal Medicine, Ehime Prefectural Hospital, Toon City, Ehime, Japan
5 Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Toon City, Ehime, Japan
Corresponding author: Yasuharu Tabara, tabara{at}m.ehime-u.ac.jp , or Haruhiko Osawa, harosawa{at}m.ehime-u.ac.jp
Abstract
OBJECTIVE— The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies
and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported
single-nucleotide polymorphisms (SNPs) from the TCF7L2 , CDKAL1 , HHEX , IGF2BP2 , CDKN2A/B , SLC30A8 , and KCNJ11 genes were analyzed.
RESEARCH DESIGN AND METHODS— Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous
association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population
sample ( n = 1,963, 61 ± 13 years).
RESULTS— In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCF7L2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility
with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 1.298–2.263). Odds ratio of other
polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding
factors.
CONCLUSIONS— Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type
2 diabetes was independent of ethnic background.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 25 November 2008.
Y.T. and H.O. contributed equally to this work.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 17, 2008.
Received December 18, 2007.
DIABETES
OBJECTIVE:Loss of the nocturnal blood pressure (BP) drop is a risk factor for cardiovascular outcomes. However, clinical parameters that predispose to changes in nocturnal BP are currently uncertain. ...Given the possible involvement of salt sensitivity in nocturnal BP levels, we investigated a hypothesized association between plasma B-type natriuretic peptide (BNP) levels – a marker of body fluid retention – and nocturnal BP in a general population.
METHODS:Study participants were 1020 general individuals. Participants were divided into four groups (riser, nondipper, dipper, and extreme dipper) by their percentage changes in nocturnal SBP measured using an ambulatory BP monitor.
RESULTS:Plasma BNP levels were positively associated with circadian BP change (β = 0.162, P < 0.001) independently of carotid hypertrophy (β = 0.133, P < 0.001), and awake heart rate (β = −0.102, P = 0.001) and SBP (β = −0.246, P < 0.001). Risers showed 1.6 times higher BNP levels than dippers, whereas oxygen desaturation during sleep was frequently observed in nondippers. Results of multinomial logistic regression analysis indicated that BNP level was a significant determinant for the riser pattern odds ratio (OR) 1.27 (BNP 10 pg/ml), P < 0.001, whereas oxygen desaturation was specifically associated with the nondipping pattern (OR 1.04, P = 0.001). When participants were subdivided by BNP level, risers were more frequent in the high BNP subgroup (19.5%) than in the low BNP subgroup (6.7%) (OR 3.39, P < 0.001).
CONCLUSION:A slight increase in plasma BNP level was independently associated with rising nocturnal BP. Our results may help to understand the pathophysiology of circadian BP variation, and be a clue to identify individuals who require careful BP monitoring.
Clinical implication of a high ankle-brachial index (ABI) is not well known. Based on our previous study, we suspected that body composition may be a determinant of a high ABI and may consequently ...modulate the clinical significance of a high ABI. Datasets of two studies with independent cohorts, the anti-aging study cohort (n = 1765) and the Nagahama study cohort (n = 8,039), were analyzed in this study, in which appendicular muscle mass was measured by computed tomography and bioelectrical impedance analysis, respectively. Brachial and ankle blood pressures were measured using a cuff-oscillometric method. In the anti-aging study cohort, thigh muscle area (β = 0.387, p < 0.001), but not fat area, showed a strong positive association with the ABI independent of the body mass index (p = 0.662) and other possible covariates, including systolic brachial blood pressure (p = 0.054), carotid hypertrophy (p = 0.559), and arterial stiffness (β = 0.102, p = 0.001). This positive association was replicated in the Nagahama cohort. When the subjects were subdivided by the 75th percentiles of the ABI and appendicular muscle mass, multinomial logistic regression analysis identified insulin resistance as an independent determinant of an elevated ABI in subjects with normal muscle mass (coefficient = 0.134, p = 0.010), whereas insulin resistance was inversely associated with an elevated ABI in subjects with high muscle mass (coefficient = -0.268, p = 0.001). Appendicular muscle mass was a strong determinant of the ABI. The clinical background, particularly insulin resistance, of individuals with an elevated ABI may differ based on the amount of muscle mass.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Serum uric acid (SUA) levels are associated with metabolic syndrome (MetS) and its components such as glucose intolerance and type 2 diabetes. It is unknown whether there are gender-specific ...differences regarding the relationship between SUA levels, impaired fasting glucose (IFG) and newly detected diabetes. We recruited 1,209 men aged 60±15 (range, 19-89) years and 1,636 women aged 63±12 (range, 19-89) years during their annual health examination from a single community. We investigated the association between SUA levels and six categories according to fasting plasma glucose (FPG) level {normal fasting glucose (NFG), <100 mg/dL; high NFG-WHO, 100 to 109 mg/dL; IFG-WHO, 110 to 125 mg/dL; IFG-ADA, 100 to 125 mg/dL; newly detected diabetes, ≥126 mg/dL; known diabetes} SUA levels were more strongly associated with the different FPG categories in women compared with men. In women, the associations remained significant for IFG-WHO (OR, 1.23, 95% CI, 1.00-1.50) and newly detected diabetes (OR, 1.33, 95% CI, 1.03-1.72) following multivariate adjustment. However, in men all the associations were not significant. Thus, there was a significant interaction between gender and SUA level for newly detected diabetes (P = 0.005). SUA levels are associated with different categories of impaired fasting glucose in participants from community-dwelling persons, particularly in women.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A paradoxical negative association between obesity and the plasma B-type natriuretic peptide (BNP) level has been firmly established. An individual's fat mass increases and muscle mass decreases with ...aging. Because aging is a potent determinant of plasma BNP levels, BNP may be related not only to fat mass but also to muscle mass. However, no studies have evaluated the associations between body composition and plasma levels of BNP. We performed a cross-sectional study to investigate these associations in 1,431 apparently healthy middle-aged to elderly subjects. The abdominal visceral fat area and thigh muscle cross-sectional area (CSA) were quantified by computed tomography. Plasma adiponectin and leptin levels were measured as possible confounding parameters. The brachial-ankle pulse wave velocity was measured as an index of arterial stiffness, and the pulse pressure (PP) of the second peak of the radial systolic blood pressure waveform (PP2) was used as an estimate of the central PP. Plasma BNP levels were significantly and negatively associated with the visceral fat area (r = −0.13, p <0.0001) and thigh muscle CSA (r = −0.25, p <0.0001). Corrections with possible confounding parameters including age, gender, heart rate, mean blood pressure, body weight, body height, adiponectin, leptin, brachial-ankle pulse wave velocity, and PP2 eliminated the association of BNP with visceral fat area but not with thigh muscle CSA (β = −0.27, p <0.0001). These findings indicate that along with adiposity, muscle mass is an independent determinant of plasma BNP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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